OBJECTIVE: It is well known that hyperoxia can be potentially harmful to the ventilated patient, although little is known about the potential effects in the setting of lung reperfusion. We hypothesized that hyperoxic ventilation at the time of reperfusion could worsen the effects of lung reperfusion injury. METHODS: Using an ex vivo, blood perfused, isolated rabbit lung system, we evaluated the effects of hyperoxic (fraction of inspired oxygen = 100%, n = 10) versus normoxic (room air, n = 10) ventilation after 18 hours of cold ischemia. Lungs were ventilated and perfused for 2 hours. A control group was immediately perfused and ventilated with a fraction of inspired oxygen of 100%. RESULTS: Lung wet/dry ratios demonstrated lower tissue edema in the normoxic group compared with in the hyperoxic group (6.72 +/- 0.89 vs 7.62 +/- 1.14 [mean +/- standard error of the mean], P = .04). Lung ventilation was also significantly better in the normoxic group versus the hyperoxic group (PCO2 = 28.96 +/- 2.01 vs 36.68 +/- 3.20 mm Hg, P = .04). Conversely, lung oxygenation after 2 hours of reperfusion (normoxic group ventilated for the last 15 minutes on 100% fraction of inspired oxygen) was not significantly different between groups (PO2 = 590.2 +/- 50.1 vs 499.6 +/- 67.5 mm Hg, P = .25). CONCLUSIONS: Ventilating lungs with 100% fraction of inspired oxygen at the time of reperfusion could increase the risk of lung reperfusion injury at the time of transplantation. Thus the patient should be ventilated with as low a fraction of inspired oxygen as possible to achieve adequate oxygen saturations during this critical reperfusion period.